Thiacycles



United States Patent 3,098,071 THIACYQLES Herbert Morton Blotter, Millburn, and George de Stevens, Willow Knoll, New Providence, NJ., assignors to Ciba Corporation, a corporation oi Delaware No Drawing. Filed Nov. 9, 1961, Ser. No. 151,148 6 Claims. (Cl. 260243) The present invention refers to novel H-l,3-thiazine compounds. More especially, it relates to compounds having one of the tautomeric structures in which R stands for hydrogen or an organic radical, and R represents an organic radical, or salts thereof, as well as process for the preparation of such compounds.

In view of the fact that the above structures are tautomeric to one another, a single compound may be assigned any of the three possible structures. Since the structure of Formula I appears to be the preferred one, the compounds of this invention will be named hereinafter as in the derivatives of 6H-l,3-thiazines, or, more specifically, as 4-hydroxy-5-R -2-(R -O)-6Hl,3-thiaZin-6-one compounds.

An organic radical representing the group R which also stands for hydrogen, may be an aliphatic radical, such as lower alkyl, having from one to ten, preferably from one to four carbon atoms, e.g. methyl, ethyl, npropyl, isopropyl, n butyl, isobutyl, secondary butyl and tertiary butyl, as well as n-pentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, 2,2,3,3-tetramethyl-butyl, 5,5-dimethyl-hexyl, n-nonyl, n-decyl and the like. Aliphatic radicals R are also lower alkenyl, e.g. vinyl, ally-l, 2- methyl-allyl, 2-butenyl and the like, or lower alkynyl, e.g.

, ethynyl, l-propynyl and the like.

R may also be a cycloaliphatic radical, such as cycloalkyl, having from three to eight, particularly from live to seven, ring carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, or cycloalkenyl having trom five to eight, especially from five to seven, ring carbon atoms, e.g. 2-cyclopentenyl, 3-cyclohexenyl, 3-cycloheptenyl and the like. Other radicals representing R are cycloaliphatic-aliphatic radicals, particularly cycloalkyl-alkyl, in which cycloalkyl has from three to eight, especially from five to seven, ring carbon atoms, and lower alkyl has from one to four carbon atoms, e.g. cyclopentyl-rnethyl, cyclohexylmethyl, Z-cyclohexyl-ethyl, 3-cyclopentyl-propyl and the like, or cycloalkenyl-lower alkyl, in which cycloalkenyl has from five to eight, especially from five to seven, ring carbon atoms, and lower alkyl has from one to four carbon atoms, e.g. 3-cyclohexenylmethyl, 2-(3-cyclohexenyl)-ethyl and the like.

3,098,071 Patented July 16,, 1963 Aliphatic radicals representing R may also have substituents; lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, may be primarily attached to cycloaliphatic radicals. Functional groups represent substituents attached to aliphatic or cycloaliphatic radicals, whereby one or more than one of the same or of dilferent groups may be present; functional groups substitute primarily lower alkyl radicals. Such functional groups are, :for example, oxygen-containing groups, such as, for example, etherified hydroxyl, particularly lower alkoxy, e.g. methoxy, ethoxy, n-p-ropyloxy, isopropyloxy, nabutyloxy, isobutyloxy and the like, as well as polyalkylenedioxy, e.g. polypropylenedioxy and the like (which groups may have trom two to twenty lower alkylenedioxy portions, and which may have a free terminal hydroxyl or an etherified terminal hydroxyl, such as a terminal lower alkoxy, e.g. methoxy, ethoxy and the like, group), carbocyclic aryloXy, such as monocyclic carbocyclic aryloxy, e.g. phenyloxy and the like, or carbocyclic aryl-lower alkyloxy, such as monocyclic carbocyclic aryl-lower alkoxy, for example, phenyl-lower alkyloXy, e.g. benzyloxy, diphenylmethoxy, (4-chlorophenyl)-phenyl-rnethoxy and the like, or esterified hydroxyl, such as lower alko-xy-carbonyloxy, e.g. methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, carbarnyloxy, such as canbamyloxy, N-lower alkyl-carbamyloxy, e.g. N-methylcarbamyloxy and the like, N,N- di-lower alkyl-car-bamyloxy, e.g. N,N-dimethyl-carbamyloxy and the like, or N-carbocyclic aryl-canbamyloxy, particularly N-monocyclic carbocyclic aryl-carbamyloxy, e.g. N-phenylcanbamyloxy and the like, or lower alkanoyloxy, e.g. acetoxy, propionyloxy and the like, lower alkanoyl, e.g. acetyl, propionyl and the like.

Functional substituents of aliphatic, particularly lower alkyl, radicals representing the group R are also nitrogencontaining groups, such as amino groups, primarily N,N- disubstituted amino, such as N,N-di-lower alkyl-amino, in which lower alkyl has from one to four carbon atoms, e.g. N,N-dimethylamino, N-ethyl-N-methylamino, N,N- diethylamino, N,N-di-n-propylamino, N,N-di-isopropylamino and the like, N-cycloalkyl-N-lower alkylamino, in which cycloalkyl has from three to eight, preferably from five to seven, ring carbon atoms, e.g. N-cyclopentyl-N- methyl-amino, N -cycloheXyl-N-methyl-amino and the like, N-carbocyclic aryl-N-lower alkyl amino, e.g. N-methyl-N- phenyl-arnino and the like, N-carbocyclic aryl-lower alkyl- N-lower alkyl-amino, such as N-lower alkyl-N-phenyllower alkyl-amino, e.g. N-benzyl-N-methyl-amino, N-

.methyl-N-(2-phenylethyl)amino and the like, or N,N-

alkylene-imino, in which alkylene has from four to six chain carbon atoms, such as, for example, lspyrrolidino, e.g. 1-pyrrolidino, Z-methyl-l-pyrrolidino and the like, l-piperidino, e.g. l-piperi-dino, 2-methyl-1piperidino, 3- methyl-l-piperidino, 4-methyl-l-piperidino, 3 hydroxy-1- piperidino, 3-acetoxy-1-piperidino, 3 hydroxymethyl-1- piperidino and the like, 1-N,N-hexa-methylene-imino and the like, N,N-oXa-alkylene-imino, in which alkylene has preferably four carbon atoms, e.g. 4-morpholino and the like, N,N-thia-alkylene-imino, in which alkylene has preferably four chain carbon atoms, e.g. 4-thiamorpholino, or N,N-aza-alkylene-imino, in which alkylene has from. four to six chain carbon atoms, particularly l-piperazino, such as 4-lower alkyl-l-piperazino, e.g. 4-methyl-1piperazino and the like, as well as piperazino, 4-(2-hydroXyethyl)-1- piperazino, 4-(Z-acetoxyethyl)-l-piperazino, 4-(2-lpolyethylenedioXy-ethyl)-1-piperazino and the like.

Sulfur-containing substituents of aliphatic, especially lower alkyl, radicals representing R are primarily etherified mercapto groups; the latter may be represented by lower alkylmercapto, e.g. methylmercapto, ethylmercapto and the like, carbocyclic aryl-mercapto, e.g. phenyl-mercapto and the like, or carbocyclic aryl-lower alkyl-mercapto, such as phenyl-lower alkyl-mercapto, e.g. benzylmercapto and the like.

Also included as substituents of aliphatic, particularly, alkyl, radicals representing R are halogeno atoms, e.g. fiuoro, chloro, bromo and the like, whereby one or more than one halogen atom may be attached to one or more than one carbon atom of an alkyl radical.

An organic radical R may also be a carbocyclic aryl, primarily a monocyclic carbocyclic aryl radical, e.g. phenyl, or a bicyclic carbocyclic aryl radical, e. g. l-naphthyl or Z-naphthyl. These radicals may be unsubstituted or may contain one or more than one of the same or different substituents attached to any of the positions available for substitution. Substituents are, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl and the like, etherified hydroxyl, such as lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, or lower alkylenedioxy, e.g. methylenedioxy and the like, esterified hydroxyl, such as lower alkoxycarbonyloxy, e.g. methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, or lower .alkanoyloxy, e.g. acetyloxy, n-propionyloxy and the like, etherified mercapto, particularly lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, esterified carboxyl, such as carbo-lower alkoxy, e.g. carbomethoxy, carbethoxy and the like, nitro, amino, particularly N,N-disubstituted amino, for example, N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, halogeno, e.g. fluoro, chloro, bromo and the like, or trifiuoromethyl and the like.

Also included as representing R are carbocyclic aryllower aliphatic radicals, primarily monocyclic carbocyclic aryl-lower alkyl, such as phenyl-lower alkyl, e.g. benzyl, diphenylmethyl, l-phenylethyl, 2-phenylethyl, 3-phenylpropyl and the like, bicyclic carbocyclic aryl-lower alkyl, such as naphthyl-lower alkyl, e.g. l-naphthylmethyl, 2-naphthylrnethyl and the like, monocyclic carbocyclic aryl-lower alkenyl, such as phenyl-lower alkenyl, e.g. 2- phenylethenyl and the like, or bicyclic carbocyclic aryllower alkenyl, such as naphthyl-lower alkenyl, e.g. 1-(2- naphthyl)-ethenyl and the like. The carbocyclic portions of these radicals may be unsubstituted or may contain substituents, such as, for example, those mentioned hereinbefore present as substituents of the carbocyclic aryl radicals.

A heterocyclic aryl radical R is primarily a monocyclic or a bicyclic heterocyclic aryl radical, which contains one or more than one sulfur, oxygen and/or nitrogen atom as ring members. Such radicals are preferably pentacyclic or hexacyclic, and are represented, for example, by pyridyl, e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl and the like, pyradazinyl, e.g. 3-pyridazinyl and the like, pyrimidyl, e.g. 2- pyrimidyl, 4-pyrimidyl and the like, pyrazinyl, e.g. 2-pyrazinyl, pyrryl, e.g. 2-pyrryl and the like, thienyl, e.g. Z-thienyl and the like, furyl, e.g. 2-furyl and the like, as well as quinolyl, e.g. Z-quinolyl and the like, isoquinolyl, e.g. l-isoquinolyl and the like, or any other suitable heterocyclic radical. The group R may also stand for a heterocyclic aryl-lower aliphatic hydrocarbon radical, such as a monocyclic or a bicyclic heterocyclic aryl-lower alkyl radical, particularly pyridyl-lower alkyl, e.g. Z-pyridylmethyl, E-pyridylmethyl, 4-pyridylmethyl, 2-(4-pyridyl)-ethyl and the like, thienyl-lower alkyl, e.g. Z-thenyl and the like, furyl-lower alkyl, e.g. 2-furylmethyl and the like, pyridazinyl-lower alkyl, e.g. 4-pyridazinylmethyl and the like, pyrimidyl-lower alkyl, e.g. Z-pyrimidylmethyl and the like, pyrazinyl-lower alkyl, e.g. 2-pyrazinylmethyl and the like, or any other analogous heterocyclic arylaliphatic radical. The above-described heterocyclic aryl radicals are unsubstituted or may contain substituents, such as lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkyl-mercapto, e.g. methyl-mercapto, ethyl-mercapto and the like, halogeno, e.g. fluoro, chloro, bromo and the like, or any other suitable substituent.

The organic group R is primarily an aliphatic radical, especially lower alkyl, having from one to seven, preferably from one to four, carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl and the like, as well as n-pentyl, n-heptyl and the like, as well as lower alkenyl, having from two to seven, preferably from three to five, carbon atoms, e.g. alkyl, 2-methylalkyl, Z-butenyl and the like. The group R may also stand for a cycloaliphatic radical, such as cycloalkyl having from three to eight, preferably from five to seven, carbon atoms, e.g. cyclopentyl, cyclohexyl and the like, or cycloalkenyl having from five to eight, preferably from five to seven, carbon atoms, e.g. 2-cyclopentenyl, 3-cyclopentenyl, 2- cyclohexenyl, 3-cyclohexenyl and the like, a cycloaliphaticaliphatic radical, such as cycloalkyl-lower alkyl, in which cycloalkyl has from three to eight, preferably from five to seven, carbon atoms, and lower alkyl has from one to seven, preferably from one to four, carbon atoms, e.g. cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, l-cyclohexylethyl and the like, or cyclo-alkenyl-lower alkyl, in which cycloalkenyl has from five to eight, preferably from five to seven, carbon atoms, and lower alkyl has from one to seven, preferably from one to four, carbon atoms, e.g. l-cyclohexenylmethyl, 1-( l-cyclohexenyl)- ethyl, 3-cyclohexenylmethyl and the like, a carbocyclic aryl radical, such as monocyclic or bicyclic carbocyclic aryl, e.g. phenyl, l-naplrthyl, Z-naphthyl, or these radicals having substituents, such as lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and the like, lower alkoxy, e.g. methoxy, ethoxy, isopropyloxy, nbutyloxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like, trifiuoromethyl and the like, carbocyclic aryl-aliphatic radical, such as monocyclic carbocyclic aryl-lower alkyl, particularly phenyl-lower alkyl, e.g. benzyl, l-phenylethyl, 2- phenylethyl, diphenylmethyl and the like, or phenyl-lower alkyl, in which phenyl has substituents, such as those previously mentioned, or any other suitable and analogous radical capable of representing the group R Salts of the compounds of this invention are primarily pharmaceutically acceptable alkali metal and alkaline earth metal salts, e.g. sodium, potassium, magnesium, calcium and the like, salts. Compounds of this invention, having basic amino groups as substituents, may form pharmaceutically acceptable acid addition salts, such as those with inorganic acids, e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acids and the like, with organic acids, e.g. acetic, propionic, glycolic, malonic, succinic, maleic, hydroxymaleic, dihydroxymaleic, fumaric, malic, tartaric, citric, salicyclic, Z-phenoxybenzoic, 2-acetoxybenzoic, acid and the like, or with organic sulfonic acids, e.g. methane sulfonic, ethane sulfonic, Z-hydroxyethane sulfonic, p-toluene sulfonic acid and the like.

The compounds of this invention have depressant effects on the central nervous system (CNS) and can, therefore, serve as tranquilizing and sedating agents in cases of overactiveness, nervousness and agitation. Advantageously, the compounds of this invention are virtually free from undesirable hypnotic side effects, they are non-addicting, and the therapeutic ratio, i.e. relationship between effective and toxic doses, is very favorable.

Particularly outstanding CNS-depressant effects are shown by the 2-lower a1kyloxy-4-hydroxy-5-R -6H-1,3- thiazin-6-ones of the formula I OH in which R represents hydrogen, an aliphatic radical, particularly lower alkyl having from one to four carbon atoms, as well as a cycloaliphatic radical, particularly cycloalkyl having from five to seven carbon atoms, or a cycloaliphatic-aliphatic radical, particularly cycloalkyllower alkyl, in which cycloalkyl has from five to seven carbon atoms and lower alkyl has from one to four carbon atoms, and R is lower alkyl, and alkali metal or alkaline earth metal salts of such compounds.

The compounds of this invention may be used in the form of pharmaceutical preparations, which contain the new compounds or salts thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration. For making up the preparations there can be employed substances which do not react with the active ingredient; suit-, able carriers may be, for example, water, gelatine, lactose, starches, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohol, gums, propylene glycol, polyalkylene glycols or any other ingredients used for pharmaceutical preparations. The latter may be in solid form, e.g. capsules, tablets, dragees and the like, or in liquid form, e.g. solutions, suspensions, emulsions and the like. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, buffers, etc. They may also contain, in combination, other useful substances.

The compounds of this invention may be prepared, for example, by treating a reactive derivative of a malonic acid, having the formula /OH lib-OH OH in which R has the previously-given meaning, with a thionocarbamate compound having one of the tautomeric formulae in which R has the previously-given meaning, and, if desired, replacing in a resulting compound, in which R stands for hydrogen, such hydrogen atom by an organic radical, and/or, if desired, converting a resulting compound into a salt thereof.

A reactive derivative of a malonic acid having the previously-given formula is more especially a malonic acid halide represented by the formula in WhichR hasthepreviously-given meaning, and each of the groups X and X stands for halogeno, e.g. chloro, bromo and the like. Other reactive derivatives of malonic acids are reactive esters, such as the 2-tetrahydropyranyl ester, as well as the lower alkyl esters, e.g. methyl, ethyl, isopropyl, tertiary butyl ester and the like. Suitable esters of a malonic acid have the formula alkoxy, e.g. methoxy, ethoxy, isopropanyloxy, tertiary butyloxy and the like. A further reactive derivative of a malonic acid is a monoester halide having the formula in which R X and R have the previously-given meanmgs.

The reaction is preferably carried out in the presence of an inert solvent, for example, methylene chloride, chloroform, carbon tetrachloride, diethyl ether, benzene, or any other suitable solvent. If desired, the reaction is performed in the presence of an inorganic or organic base, such as an alkali metal salt of an organic carboxylic acid, e.g. sodium acetate and the like, an alkali metal lower alkanolate, e.g. sodium or potassium methanolate, ethanolate, tertiary butanolate and the like, or any other suitable base, such as a tertiary amine, e.g. N,N,N-triethylamine, pyridine and the like, if necessary, while cooling or at an elevated temperature, in a closed vessel and/or in the atmosphere of an inert gas, e.g. nitrogen.

The starting materials are known or may be prepared according to known methods.

The compounds of the present invention may also be prepared by ring-closing a compound having one of the tautomeric formulae and in which R and R have the previously-given meaning,

suitable reagent, such as, for example, an N,N'-di-substituted carbodiimide, e.g. N,N-di-cyclohexyl-carbodiimide and the like. Other ring closing reagents are, for example, inorganic acid halides, e.g. thionyl chloride, phosphorous pen-tachloride and the like, or inorganic or organic bases, such'as, for example, an alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, an alkali metal lower alkanolate, e.g. sodium or potassium methanolate, ethanolate, tertiary butanolate and the like, an organic amine, e.g. N,N,N-triethylamine and the like, pyridine, or any other equivalent reagent. Treatment with the reagent is preferably carried out in the presence of a suitable inert solvent, and, if desired, while ethyl ether.

cooling or at an elevated temperature, in a closed vessel and/or in the atmosphere of nitrogen.

The starting materials may be prepared according to known methods, for example, by reacting, a malonic acid halide monoester, such as a malonic acid chloride monolower alkyl-ester, with a suitable metal thiocyanate compound, such as, for example, lead thiocyanate and the like, and then with a suitable hydroxylated compound, such as a lower alkanol, e.g. ethanol and the like, or with a lower alkyl thionocarbamate, e.g. ethyl thionocarbamate and the like, and, if necessary, converting the ester group into a free carboxyl group by hydrolysis.

In a resulting compound, in which the group R stands for hydrogen, such hydrogen atom may be replaced by an organic radical, particularly an aliphatic or a substituted aliphatic radical, according to known methods, for example, by forming a metal salt, such as an alkali metal, e.g. sodium, potassium and the like, salt of a resulting compound, in which R is hydrogen, and reacting the salt with a reactive ester of an organic hydroxyl compound, particularly the reactive ester of an aliphatic or substituted aliphatic hydroxyl compound, especially with an organic halogeno compound, such as an aliphatic or substituted aliphatic halogeno compound.

A resulting compound may be converted into an alkali metal salt or an alkaline earth metal salt according to known methods, for example, by treating it or a solution thereof with a metal hydroxide or hydride, preferably used in admixture with a solvent, and evaporating the diluent.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example 1 A solution of 6.3 g. of ethyl thionocarbamate in 75 ml. of dry methylene chloride in added dropwise over a period of three hours to a solution of 8.46 g. of malonic acid dichloride in 45 ml. of dry methylene chloride while stirring and maintaining an atmosphere of nitrogen. The reaction proceeds at room temperature, and after completing the addition, stirring is continued for an additional hour. The resulting precipitate is filtered off and the desired 2-ethoxy-4-hydroxy-6H-1,3-thiazin-6-one of the formula i i is purified by crystallizing the crude product twice from a mixture of diethyl ether and n-pentane using a charcoal decolorizing preparation; M.P. 129-l32.

Example 2 To 0.95 g. of N-(ethoxythiocarbonyl)-rnalonamic acid in 50 ml. of dry diethyl ether is added a solution of 1.1 g. of N,N'-dicyclohexylcarbodiimide in ml. of dry di- The mixture is allowed to stand for one hour, the precipitate is filtered olf, and the filtrate is concentrated. Dry n-pentane is added, whereupon 0.15 g. of the desired 2-ethoxy-4-hydroxy-6H-1,3-thiazin-6-one precipitates; the compound melts at l29131 and is identical with the product of Example 1.

The starting material used in the above reaction may be prepared, for example, by reacting malonic acid monotertiary butyl ester with lead thiocyanate and then with ethanol, and hydrolyzing the tertiary butyl ester group by treatment with a small amount of hydrochloric acid.

Other compounds, which are prepared according to the above methods are, for example, 2-ethoxy-4-hydroxy-5- methyl-6H-1,3-thiazin-4-one, S-ethyl-4-hydroxy-2-methoxy-6H-l,3-thiazin-4-one, 4-hydroxy-5-isopropyl-2-methoxy 6H 1,3 thiazin 4 one, 5 cyclohexyl 2 ethoxy-4-hydroxy-6H-l,3-thiazin-4-one, S-cyclopentylmethyl- 2-ethoxy-4-hydroxy-6H-1,3-thiazin-4-one and the like.

What is claimed is:

1. A member selected from the group consisting of a compound having one of the formulae selected from the group consisting of and in which R stands for a member selected from the group consisting of hydrogen, lower alkyl, cycloalkyl having from three to eight carbon atoms, and cycloalkyl-lower alkyl, in which cycloalkyl has from three to eight carbon atoms, and R is lower alkyl, an alkali metal salt thereof and an alkaline earth metal salt thereof.

2. A compound having the formula in which R is hydrogen, and R is lower alkyl.

3. The compound having the formula in which R is lower alkyl, and R is lower alkyl.

4. The compound having the formula in which R is cycloalkyl having from three to eight carbon atoms, and R is lower alkyl.

5. 2-ethoxy-4-hydroxy-6H-1,3-thiazin-6-one.

9 6. The compound of the formula 10 in which R is cycloalkyl-lower alkyl, in which cycloalkyl has from three to eight carbon atoms, and R is lower alkyl.

5 References Cited in the file of this patent Goerdeler et a1.: Berichte, volume 93, pages 671-8 (1960). 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND HAVING ONE OF THE FOEMULAE SELECTED FRROM THE GROUP CONSISTING OF 